Heterocyclic compounds and methods of use

ABSTRACT

Compounds of the formula  
                 
 
     provide pharmacological agents which are potent agonists of Peroxisome Proliferator-Activated Receptors (PPARs). Accordingly, the compounds of the instant invention are useful for the treatment of conditions mediated by the PPAR receptor activity in mammals. Such conditions include dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer&#39;s disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, ulcerative colitis and Crohn&#39;s disease. The compounds of the present invention are particularly useful in mammals as hypoglycemic agents for the treatment and prevention of conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X. Preferred are the compounds of the invention which are dual agonists of PPARα and PPARγ receptors.

[0001] The present invention relates to heterocyclic compounds,pharmaceutical compositions containing them and to methods of treatingconditions associated with the Retinoid X Receptor (RXR) and thePeroxisome Proliferator-Activated Receptor (PPAR) families with thethree subtypes PPARα, PPARδ and PPARγ.

[0002] In one aspect the present invention provides compounds of theformula

[0003] wherein

[0004] L is

[0005]  radical in which R₁ is hydrogen, optionally substituted alkyl,aryl, heteroaryl, aralkyl or cycloalkyl;

[0006] R₂ is hydrogen, hydroxy, optionally substituted alkyl, aryl,aralkyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio or aralkylthio;

[0007] R₃ is hydrogen or aryl; or

[0008] R₂ and R₃ combined are alkylene which together with the carbonatoms they are attached to form a 5- to 7-membered ring;

[0009] n is zero or an integer from 1 to 2;

[0010] Y is hydrogen; or

[0011] Y and R₂ taken together with the carbon atoms they are attachedto form a bond provided that n is 1;

[0012] R₄ is hydrogen; or

[0013] R₄ and Y taken together with the carbon atoms they are attachedto form a bond provided that n is 1, and R₂ and R₃ taken together withthe carbon atoms they are attached to form a bond; or

[0014] L is

[0015]  radical in which R₁ is hydrogen, optionally substituted alkyl,aryl, heteroaryl, aralkyl or cycloalkyl;

[0016] R″ is hydrogen, optionally substituted alkyl, alkoxy or halogen;

[0017] m is an integer from 1 to 2;

[0018] Y is hydrogen;

[0019] R₄ is hydrogen; or

[0020] R₄ and Y taken together with the carbon atoms they are attachedto form a bond provided that m is 1;

[0021] R and R′ are independently hydrogen, halogen, optionallysubstituted alkyl, alkoxy, aralkyl or heteroaralkyl; or

[0022] R and R′ combined together form a methylenedioxy group providedthat R and R′ are attached to carbon atoms adjacent to each other; or

[0023] R and R′ combined together with the carbon atoms they areattached to form an optionally substituted 5- to 6-membered aromatic orheteroaromatic ring provided that R and R′ are attached to carbon atomsadjacent to each other; or

[0024] R—C and R′—C may independently be replaced by nitrogen;

[0025] X is -Z-(CH₂)_(p)-Q-W wherein Z is a bond, O, S, S(O), S(O)₂,—C(O)— or —C(O)NR₅— in which

[0026] R₅ is hydrogen, alkyl or aralkyl;

[0027] p is an integer from 1 to 8;

[0028] Q is a bond provided that Z is not a bond when p is 1; or

[0029] Q is —O(CH₂)_(r)— or —S(CH₂)_(r)— in which r is zero or aninteger from 1 to 8; or

[0030] Q is —O(CH₂)₁₋₈O—, —S(CH₂)₁₋₈O—, —S(CH₂)₁₋₈S—, —C(O)— or—C(O)NR₆— in which R₆ is hydrogen, optionally substituted alkyl,cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or

[0031] Q is —NR₆—, —NR₅C(O)—, —NR₅C(O)NH— or —NR₅C(O)O— provided that pis not 1;

[0032] W is cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; or

[0033] W and R₆ taken together with the nitrogen atom to which they areattached form a 8- to 12-membered bicyclic ring, which may be optionallysubstituted or may contain another heteroatom selected from oxygen,nitrogen and sulfur;

[0034] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0035] In another aspect the present invention provides methods oftreating conditions mediated by the PPAR receptor activity in mammals.Such conditions include dyslipidemia, hyperlipidemia,hypercholesteremia, atherosclerosis, hypertriglyceridemia, heartfailure, myocardial infarction, vascular diseases, cardiovasculardiseases, hypertension, obesity, inflammation, arthritis, cancer,Alzheimer's disease, skin disorders, respiratory diseases, ophthalmicdisorders, IBDs (irritable bowel disease), ulcerative colitis andCrohn's disease. The compounds of the present invention are particularlyuseful in mammals as hypoglycemic agents for the treatment andprevention of conditions in which impaired glucose tolerance,hyperglycemia and insulin resistance are implicated, such as type-1 andtype-2 diabetes and Syndrome X. Preferred are the compounds of theinvention which are dual agonists of PPARα and PPARγ receptors.

[0036] The present invention relates to heterocyclic compounds,pharmaceutical compositions containing them, methods for preparing thecompounds and methods of treating conditions mediated by the RXR and thePPAR families, including activation of PPARs, using such compounds. Thecompounds of the invention may also be used in combination with ligandsfor other nuclear receptors which are known to form heterodimericcomplexes with the RXR receptors.

[0037] Further, the present invention relates to pharmaceuticalcompositions containing the heterocyclic compounds of the invention forthe treatment of the conditions mentioned hereinabove.

[0038] Listed below are definitions of various terms used to describethe compounds of the instant invention. These definitions apply to theterms as they are used throughout the specification and the claimsunless they are otherwise limited in specific instances eitherindividually or as part of a larger group, e.g., wherein an attachmentpoint of a certain group is limited to a specific atom within thatgroup, the point of attachment is defined by an arrow at the specificatom.

[0039] The term “optionally substituted alkyl” refers to unsubstitutedor substituted straight or branched chain hydrocarbon groups having 1 to20 carbon atoms, preferably 1 to 7 carbon atoms. Exemplary unsubstitutedalkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl andthe like. Substituted alkyl groups include, but are not limited to,alkyl groups substituted by one or more of the following groups: halo,hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy,amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio,alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,sulfonamido, nitro, cyano, carboxy, alkoxycarbonyl, aryl, alkenyl,alkynyl, aralkoxy, guanidino, heterocyclyl including indolyl,imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl,piperidyl, morpholinyl and the like.

[0040] The term “lower alkyl” refers to those alkyl groups as describedabove having 1 to 7, preferably 1 to 4 carbon atoms.

[0041] The term “halogen” or “halo” refers to fluorine, chlorine,bromine and iodine.

[0042] The term “alkenyl” refers to any of the above alkyl groups havingat least two carbon atoms and further containing a carbon to carbondouble bond at the point of attachment. Groups having two to four carbonatoms are preferred.

[0043] The term “alkynyl” refers to any of the above alkyl groups havingat least two carbon atoms and further containing a carbon to carbontriple bond at the point of attachment. Groups having two to four carbonatoms are preferred.

[0044] The term “alkylene” refers to a straight chain bridge of 1 to 6carbon atoms connected by single bonds (e.g., —(CH₂)_(x)— wherein x is 1to 6), which may be substituted with 1 to 3 lower alkyl or alkoxygroups.

[0045] The term “cycloalkyl” refers to optionally substitutedmonocyclic, bicyclic or tricyclic hydrocarbon groups of 3 to 12 carbonatoms, each of which may optionally be substituted by one or moresubstituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl,amino, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano,carboxy, carboxyalkyl, alkoxycarbonyl, alkyl- and arylsulfonyl,sulfonamido, heterocyclyl and the like.

[0046] Exemplary monocyclic hydrocarbon groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl and cyclohexenyl and the like.

[0047] Exemplary bicyclic hydrocarbon groups include bornyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like.

[0048] Exemplary tricyclic hydrocarbon groups include adamantyl and thelike.

[0049] The term “alkoxy” refers to alkyl-O—.

[0050] The term “acyl” refers to alkanoyl, aroyl, heteroaroyl,arylalkanoyl or heteroarylalkanoyl.

[0051] The term “alkanoyl” refers to alkyl-C(O)—.

[0052] The term “alkanoyloxy” refers to alkyl-C(O)—O—.

[0053] The terms “alkylamino” and “dialkylamino” refer to alkyl-NH— and(alkyl)₂N—, respectively.

[0054] The term “alkanoylamino” refers to alkyl-C(O)—NH—.

[0055] The term “alkylthio” refers to alkyl-S—.

[0056] The term “alkylaminothiocarbonyl” refers to alkyl-NHC(S)—.

[0057] The term “trialkylsilyl” refers to (alkyl)₃Si—.

[0058] The term “trialkylsilyloxy” refers to (alkyl)₃SiO—.

[0059] The term “alkylthiono” refers to alkyl-S(O)—.

[0060] The term “alkylsulfonyl” refers to alkyl-S(O)₂—.

[0061] The term “alkoxycarbonyl” refers to alkyl-O—C(O)—.

[0062] The term “alkoxycarbonyloxy” refers to alkyl-O—C(O)O—.

[0063] The term “carbamoyl” refers to alkyl-NHC(O)—, (alkyl)₂NC(O)—,aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aralkyl-NHC(O)— and alkyl(aralkyl)-NC(O)—.

[0064] The term “aryl” refers to monocyclic or bicyclic aromatichydrocarbon groups having 6 to 12 carbon atoms in the ring portion, suchas phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups,each of which may optionally be substituted by one to four substituents,such as alkyl, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, optionallysubstituted amino, thiol, alkylthio, nitro, cyano, carboxy,carboxyalkyl, alkoxycarbonyl, alkylthiono, alkyl- and arylsulfonyl,sulfonamido, heterocycloyl and the like.

[0065] The term “monocyclic aryl” refers to optionally substitutedphenyl as described under aryl.

[0066] The term “aralkyl” refers to an aryl group bonded directlythrough an alkyl group, such as benzyl.

[0067] The term “aralkylthio” refers to aralkyl-S—.

[0068] The term “aralkoxy” refers to an aryl group bonded directlythrough an alkoxy group.

[0069] The term “arylsulfonyl” refers to aryl-S(O)₂—.

[0070] The term “arylthio” refers to aryl-S—.

[0071] The term “aroyl” refers to aryl-C(O)—.

[0072] The term “aroylamino” refers to aryl-C(O)—NH—.

[0073] The term “aryloxycarbonyl” refers to aryl-O—C(O)—.

[0074] The term “heterocyclyl” or “heterocyclo” refers to an optionallysubstituted, fully saturated or unsaturated, aromatic or non-aromaticcyclic group, for example, which is a 4- to 7-membered monocyclic, 7- to12-membered bicyclic, or 10- to 15-membered tricyclic ring system, whichhas at least one heteroatom in at least one carbon atom-containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized. The heterocyclic group may be attached at a heteroatom or acarbon atom.

[0075] Exemplary monocyclic heterocyclic groups include pyrrolidinyl,pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl and the like.

[0076] Exemplary bicyclic heterocyclic groups include indolyl,dihydroidolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl,benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl,decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), phthalazinyl and the like.

[0077] Exemplary tricyclic heterocyclic groups include carbazolyl,dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl,carbolinyl and the like.

[0078] The term “heterocyclyl” includes substituted heterocyclic groups.Substituted heterocyclic groups refer to heterocyclic groups substitutedwith 1, 2 or 3 of the following:

[0079] (a) alkyl;

[0080] (b) hydroxy (or protected hydroxy);

[0081] (c) halo;

[0082] (d) oxo (i.e.=O);

[0083] (e) optionally substituted amino, alkylamino or dialkylamino;

[0084] (f) alkoxy;

[0085] (g) cycloalkyl;

[0086] (h) carboxy;

[0087] (i) heterocyclooxy;

[0088] (j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl;

[0089] (k) mercapto;

[0090] (l) nitro;

[0091] (m) cyano;

[0092] (n) sulfonamido, sulfonamidoalkyl, sulfonamidoaryl orsulfonamidodialkyl;

[0093] (o) aryl;

[0094] (p) alkylcarbonyloxy;

[0095] (q) arylcarbonyloxy;

[0096] (r) arylthio;

[0097] (s) aryloxy;

[0098] (t) alkylthio;

[0099] (u) formyl;

[0100] (v) carbamoyl;

[0101] (w) aralkyl; or

[0102] (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy,amino, alkylamino, dialkylamino or halo.

[0103] The term “heterocyclooxy” denotes a heterocyclic group bondedthrough an oxygen bridge.

[0104] The term “heteroaryl” refers to an aromatic heterocycle, forexample monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzofuryl and the like; optionally substituted by,e.g., lower alkyl, lower alkoxy or halo.

[0105] The term “heteroarylsulfonyl” refers to heteroaryl-S(O)₂—.

[0106] The term “heteroaroyl” refers to heteroaryl-C(O)—.

[0107] The term “heteroaralkyl” refer to a heteroaryl group bondedthrough an alkyl group.

[0108] Encompassed by the invention are prodrug derivatives, e.g., anypharmaceutically acceptable prodrug ester derivatives of the carboxylicacids of the invention which are convertible by solvolysis or underphysiological conditions to the free carboxylic acids.

[0109] Examples of such carboxylic acid esters are preferably loweralkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters,mono or disubstituted lower alkyl esters, e.g., the ω-(amino, mono- ordi-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters,the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-loweralkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxy-methylester, and the like conventionally used in the art.

[0110] The compounds of the invention depending on the nature of thesubstituents, may possess one or more asymmetric centers. The resultingdiastereoisomers, optical isomers, i.e., enantiomers, and geometricisomers are encompassed by the instant invention.

[0111] Preferred are compounds of the formula I wherein

[0112] X is -Z-(CH₂)_(p)-Q-W wherein Z is a bond, O, S, —C(O)— or—C(O)NR₅— in which

[0113] R₅ is hydrogen, alkyl or aralkyl;

[0114] p is an integer from 1 to 8;

[0115] Q is a bond provided that Z is not a bond when p is 1; or

[0116] Q is —O(CH₂)_(r)— or —S(CH₂)_(r)— in which r is zero or aninteger from 1 to 8; or

[0117] Q is —O(CH₂)₁₋₈O—, —S(CH₂)₁₋₈, —S(CH₂)₁₋₈S—, —C(O)— or —C(O)NR₆—in which R₆ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl,heteroaryl, aralkyl or heteroaralkyl; or

[0118] Q is —NR₆—, —NR₅C(O)—, —NR₅C(O)NH— or —NR₅C(O)O— provided that pis not 1;

[0119] W is cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; or

[0120] W and R₆ taken together with the nitrogen atom to which they areattached form a 8- to 12-membered bicyclic ring, which may be optionallysubstituted or may contain another heteroatom selected from oxygen,nitrogen and sulfur;

[0121] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0122] Further preferred are compounds of the formula

[0123] wherein

[0124] L is

[0125]  radical in which R₁ is hydrogen or optionally substituted alkyl;

[0126] R₂ and R₃ are hydrogen; or

[0127] R₂ and R₃ combined are alkylene which together with the carbonatoms they are attached to form a 6-membered ring;

[0128] n is zero or an integer from 1 to 2;

[0129] Y is hydrogen;

[0130] R₄ is hydrogen; or

[0131] L is

[0132]  radical in which R₁ is hydrogen or optionally substituted alkyl;

[0133] R″ is hydrogen, optionally substituted alkyl, alkoxy or halogen;

[0134] m is an integer from 1 to 2;

[0135] Y is hydrogen;

[0136] R₄ is hydrogen;

[0137] R and R′ are independently hydrogen, halogen, optionallysubstituted C₁₋₆alkyl or C₁₋₆alkoxy; or

[0138] R and R′ combined together form a methylenedioxy group providedthat R and R′ are attached to carbon atoms adjacent to each other;

[0139] Z is a bond, O, S or —C(O)NR₅— in which R₅ is hydrogen, alkyl oraralkyl;

[0140] p is an integer from 1 to 5;

[0141] Q is a bond provided that Z is not a bond when p is 1; or

[0142] Q is —O(CH₂)_(r)— or —S(CH₂)_(r)— in which r is zero; or

[0143] Q is —C(O)— or —C(O)NR₆— in which R₆ is hydrogen, optionallysubstituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl orheteroaralkyl; or

[0144] Q is —NR₆—, —NR₅C(O)—, —NR₅C(O)NH— or —NR₅C(O)O— provided that pis not 1;

[0145] W is cycloalkyl, aryl or heterocyclyl; or

[0146] W and R₆ taken together with the nitrogen atom to which they areattached form a 9- to 10-membered bicyclic ring, which may be optionallysubstituted or may contain another heteroatom selected from oxygen,nitrogen and sulfur;

[0147] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0148] More preferred are the compounds of the formula IA wherein

[0149] L is

[0150]  radical in which R₁ is hydrogen or optionally substituted alkyl;

[0151] R₂ and R₃ are hydrogen;

[0152] n is zero or an integer from 1 to 2; or

[0153] L is

[0154]  radical in which R₁ is hydrogen or optionally substituted alkyl;

[0155] R″ is hydrogen;

[0156] m is an integer from 1 to 2;

[0157] R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy;

[0158] R′ is hydrogen;

[0159] Z is a bond, O or S;

[0160] p is an integer from 1 to 5;

[0161] Q is a bond provided that Z is not a bond when p is 1; or

[0162] Q is O, S or —C(O)NR₆— in which R₆ is hydrogen, optionallysubstituted alkyl or cycloalkyl; or

[0163] Q is —NR₆—, —NR₅C(O)NH— or —NR₅C(O)O— in which R₅ is hydrogen,alkyl or aralkyl provided that p is not 1;

[0164] W is cycloalkyl, aryl or heterocyclyl; or

[0165] W and R6 taken together with the nitrogen atom to which they areattached form a 9- to 10-membered bicyclic ring, which may be optionallysubstituted or may contain another heteroatom selected from oxygen,nitrogen and sulfur;

[0166] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0167] Most preferred are the compounds of the formula

[0168] wherein

[0169] L is

[0170]  radical in which R₁ is hydrogen or optionally substituted alkyl;

[0171] n is zero or 1; or

[0172] L is

[0173]  radical in which R₁ is hydrogen or optionally substituted alkyl;

[0174] m is 1;

[0175] R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy;

[0176] Z is a bond, O or S;

[0177] p is an integer from 1 to 5;

[0178] Q is a bond provided that Z is not a bond when p is 1; or

[0179] Q is O, S or —C(O)NR₆— in which R₆ is hydrogen, optionallysubstituted alkyl or cycloalkyl; or

[0180] Q is —NR₆—, —NR₅C(O)NH— or —NR₅C(O)O— in which R₅ is hydrogen,alkyl or aralkyl provided that p is not 1;

[0181] W is cycloalkyl, aryl or heterocyclyl; or

[0182] W and R₆ taken together with the nitrogen atom to which they areattached form a 9- to 10-membered bicyclic ring, which may be optionallysubstituted or may contain another heteroatom selected from oxygen,nitrogen and sulfur;

[0183] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0184] Further preferred are compounds of formula IB wherein

[0185] L is

[0186]  radical in which R₁ is hydrogen; and n is zero or 1;

[0187] R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy;

[0188] Z is a bond, O or S;

[0189] p is an integer from 1 to 4;

[0190] Q is a bond provided that Z is not a bond when p is 1; or

[0191] Q is O or S;

[0192] W is aryl or heterocyclyl;

[0193] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0194] Further preferred are also the compounds of formula IB wherein

[0195] L is

[0196]  radical in which R₁ is hydrogen;

[0197] R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy;

[0198] Z is a bond, O or S;

[0199] p is an integer from 1 to 4;

[0200] Q is a bond provided that Z is not a bond when p is 1; or

[0201] Q is O or S;

[0202] W is aryl or heterocyclyl;

[0203] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0204] Further preferred are also the compounds of formula IB whereinthe asymmetric center in radical L is in the (R) configuration; or apharmaceutically acceptable salt thereof.

[0205] Further preferred are also the compounds of formula IB,designated as the A group, wherein

[0206] R₁ is hydrogen or optionally substituted alkyl;

[0207] R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy;

[0208] Z is O or S;

[0209] p is 2;

[0210] Q is a —NR₆— in which R₆ is lower alkyl;

[0211] W is aryl or heterocyclyl;

[0212] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0213] Preferred are the compounds in the A group wherein

[0214] R is hydrogen, chloro, n-propyl or methoxy;

[0215] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0216] Further preferred are also the compounds of formula IB,designated as the B group, wherein

[0217] R₁ is hydrogen or optionally substituted alkyl;

[0218] R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy;

[0219] Z is a bond;

[0220] p is 2;

[0221] Q is a —C(O)NR₆— in which R₆ is optionally substituted alkyl;

[0222] W is aryl or heterocyclyl; or

[0223] W and R₆ taken together with the nitrogen atom to which they areattached form a 9- to 10-membered bicyclic ring, which may be optionallysubstituted or may contain another heteroatom selected from oxygen,nitrogen and sulfur;

[0224] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0225] Preferred are the compounds in the B group wherein

[0226] R is hydrogen, chloro, n-propyl or methoxy;

[0227] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0228] Further preferred are also the compounds of formula IB,designated as the C group, wherein

[0229] R₁ is hydrogen or optionally substituted alkyl;

[0230] R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy;

[0231] Z is a bond, O or S;

[0232] p is an integer from 2 to 3;

[0233] Q is O or S;

[0234] W is aryl or heterocyclyl;

[0235] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0236] Preferred are the compounds in the C group wherein

[0237] R is hydrogen, chloro, n-propyl or methoxy;

[0238] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0239] Another preferred group of compounds in the C group are thecompounds wherein

[0240] W is selected from the group consisting of:

[0241] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0242] Further preferred are also the compounds of formula IB,designated as the D group, wherein

[0243] R₁ is hydrogen or optionally substituted alkyl;

[0244] R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy;

[0245] Z is O or S;

[0246] p is an integer from 1 to 2;

[0247] Q is a bond;

[0248] W is aryl or heterocyclyl;

[0249] or a pharmaceutically acceptable salt thereof; or an opticalisomer or a mixture of optical isomers thereof.

[0250] Preferred are the compounds in the D group wherein R is hydrogen,chloro, n-propyl or methoxy;

[0251] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0252] Another preferred group of compounds in the D group are thecompounds wherein

[0253] W is selected from the group consisting of:

[0254] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0255] Yet another preferred group of compounds in the D group are alsothe compounds, wherein

[0256] R₁ is hydrogen or optionally substituted alkyl;

[0257] R is hydrogen, halogen, optionally substituted C₁₋₆ alkyl or C₁₋₆alkoxy;

[0258] Z is O or S;

[0259] p is 2;

[0260] Q is a bond;

[0261] W is selected from the group consisting of:

[0262] or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof.

[0263] Particular embodiments of the invention are:

[0264](R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-azetidine-2-carboxylicacid;

[0265](R)-1-(4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl)-azetidine-2-carboxylicacid;

[0266](R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-azetidine-2-carboxylicacid;

[0267](R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-azetidine-2-carboxylicacid;

[0268](R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-azetidine-2-carboxylicacid;

[0269](R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene-sulfonyl}-azetidine-2-carboxylicacid;

[0270](R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-azetidine-2-carboxylicacid;

[0271](R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0272](R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0273](R)-1-(4-{3-[2-Propyl-4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}-benzenesulfonyl)-pyrrolidine-2-carboxylicacid;

[0274](R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0275](R)-1-(4-{2-[2-Propyl-4-(4-trifluoromethyl-phenoxy)-phenoxy]-ethoxy}-benzenesulfonyl)-pyrrolidine-2-carboxylicacid;

[0276](R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0277](R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0278](R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-3-propyl-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0279](R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0280](R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0281](R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0282](R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;

[0283] (R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0284](R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0285](R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene-sulfonyl}-pyrrolidine-2-carboxylicacid;

[0286](R)-1-[4-(2-Biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;

[0287](R)-1-[3-Methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;

[0288](R)-1-[3-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;

[0289](R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-3-propyl-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;

[0290](R)-1-[4-(5-Methyl-2-pheny-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;

[0291](R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0292](R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0293](R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0294](R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0295](R)-1-{3-Methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}pyrrolidine-2-carboxylicacid;

[0296](R)-1-{3-Chloro-4-[2-(5-methyl-2-phenyi-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0297](R)-1-(4-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-benzenesulfonyl)-pyrrolidine-2-carboxylicacid;

[0298](R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yI)-ethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;

[0299](R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0300](R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0301](R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0302](R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0303](R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0304](R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid;

[0305](R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0306](R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0307](R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene-sulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid;

[0308](R)-1-[3-Methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid;

[0309](R)-1-[3—Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid;

[0310](R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-3-propyl-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid;

[0311](R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid;

[0312](R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0313](R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0314](R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0315](R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid; and

[0316](R)-1-{3-Chloro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0317](R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzene-sulfonyl}-pyrrolidine-2-carboxylicacid;

[0318](R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzene-sulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;

[0319] or a pharmaceutically acceptable salt thereof; or an enantiomerthereof; or a mixture of enantiomers thereof.

[0320] Pharmaceutically acceptable salts of any acidic compounds of theinvention are salts formed with bases, namely cationic salts such asalkali and alkaline earth metal salts, such as sodium, lithium,potassium, calcium, magnesium, as well as ammonium salts, such asammonium, trimethylammonium, diethylammonium, andtris-(hydroxymethyl)-methyl-ammonium salts.

[0321] Similarly acid addition salts, such as of mineral acids, organiccarboxylic and organic sulfonic acids, e.g., hydrochloric acid,methanesulfonic acid, maleic acid, are possible provided a basic group,such as pyridyl, constitutes part of the structure.

[0322] Compounds of formula I may be prepared starting from sulfonicacid analogs of the formula

[0323] in which R and R′ have meanings as defined herein, X′ representsX as defined herein, or X′ is a group convertible to X. Compounds offormula II may be first treated with a chlorinating agent, such asthionyl chloride or oxalyl chloride to form sulfonyl chlorides of theformula

[0324] wherein R, R′ and X′ have meanings as defined herein above, usingreaction conditions described herein, or using conditions well-known inthe art.

[0325] Sulfonyl chlorides of formula III wherein R, R′ and X′ havemeanings as defined herein above can then be reacted with amines of theformula

[0326] in which R₁, R₂, R₃, R₄, n, Y, R″ and m have meanings as definedherein, in the presence of a base, such as triethylamine,diisopropylethylamine or N-methylmorpholine in an inert solvent, such asdichloromethane, N,N-dimethylformamide or tetrahydrofuran to obtaincompounds of the formula

[0327] wherein R, R′ and X′ have meanings as defined herein above and Lrepresents

[0328] radical wherein R₁, R₂, R₃, R₄, n, Y, R″ and m have meanings asdefined herein above. Amines of formula IV and V may be obtained bymethods described herein or modifications thereof, or by methods knownin the art.

[0329] Compounds of formula I′ wherein X′ represents X as defined hereincan be obtained from compounds of formula I′ wherein X′ is a groupconvertible to X using methods described herein or modificationsthereof, or using methods well known in the art. For example, compoundsof formula I′ in which X′ is benzyloxy can be first converted tocompounds of the formula

[0330] wherein R, R′ and L have meanings as defined herein above, e.g.,by reduction with hydrogen in the presence of a catalyst, such aspalladium on carbon in a polar organic solvent, such as ethyl acetate orethanol. The resulting phenols of the formula VI may then be treatedwith an alkylating agent of the formula

Lg-(CH₂)_(p)-Q-W  (VII)

[0331] wherein p, Q and W have meanings as defined herein and Lgrepresents a leaving group such as bromide, chloride ortrifluoromethanesulfonate, in the presence of a base, such as potassiumcarbonate or sodium hydride in an inert solvent, such asN,N-dimethylformamide or tetrahydrofuran to form compounds of formula I′in which X′ is —O—(CH₂)_(p)-Q-W and p, Q and W have meanings as definedherein.

[0332] Alternatively, compounds of formula I′ wherein X′ is—O—(CH₂)_(p)-Q-W, and p, Q and W have meanings as defined herein may beobtained from sulfonic acid analogs of formula II in which X′ ishydroxy, and R and R′ have meanings as defined herein, by converting acompound of formula II to its dialkali metal salt, e.g., a disodiumsalt, using aqueous base, e.g., aqueous sodium hydroxide, in a polarsolvent, such as 1,4-dioxane, followed by treatment with an alkylatingagent of formula VII wherein p, Q and W have meanings as defined hereinand Lg represents a leaving group, such as bromide, chloride ortrifluoro-methanesulfonate to form compounds of the formula

[0333] wherein R, R′, p, Q and W have meaning as defined herein.

[0334] Compounds of formula VIII wherein R, R′, p, Q and W have meaningas defined herein may be treated with a chlorinating agent, such asthionyl chloride or oxalyl chloride to afford sulfonyl chlorides of theformula

[0335] wherein R, R′, p, Q and W have meaning as defined herein.Sulfonyl chlorides of formula IX can be reacted with amines of formulaeIV or V, or acid addition salts thereof, in which R₁ is hydrogen, andR₂, R₃, n, Y, R″ and m have meanings as defined herein, in the presenceof a base such as aqueous sodium hydroxide in a polar solvent, such as1,4-dioxane to form compounds of formula I′ in which X′ is—O—(CH₂)_(p)-Q-W and p, Q and W have meanings defined herein.

[0336] Similarly, compounds of formula I′ wherein R, R′ and L havemeanings as defined herein above, and X′ is thiol can be converted tocompounds of formula I′ in which X′ is —S—(CH₂)_(p)-Q-W. For example,thiols of the formula

[0337] wherein R and R′ have meanings as defined herein may be dimerizedby methods well known in the art to form disulfides of the formula

[0338] wherein R and R′ have meanings as defined herein.

[0339] Compounds of formula XI wherein R and R′ have meanings as definedherein can be converted to bis sulfonylchloride analogs of the formula

[0340] wherein R and R′ have meanings as defined herein, by treatmentwith chlorosulfonic acid in an inert solvent, such as dichloromethanefollowed by basic hydrolysis using, e.g., aqueous sodium hydroxide. Theresulting bis sodium salts can then be treated with a chlorinatingagent, such as thionyl chloride or oxalyl chloride to form sulfonylchlorides of formula XII.

[0341] Sulfonyl chlorides of formula XII wherein R and R′ have meaningsas defined herein may be reacted with amines of the formula

[0342] in which R₁, R₂, R₃, R₄, n, Y, R″ and m have meanings as definedherein, in the presence of a base, such as triethylamine,diisopropylethylamine or N-methylmorpholine in an inert solvent, such asdichloromethane, N,N-dimethylformamide or tetrahydrofuran to afforddisulfides of the formula

[0343] wherein R and R′ have meanings as defined herein above and Lrepresents

[0344] radical wherein R₁, R₂, R₃, R₄, n, Y, R″ and m have meanings asdefined herein above.

[0345] Disulfides of formula XIII wherein R, R′ and L have meanings asdefined herein can be reduced to thiols of the formula

[0346] wherein R, R′ and L have meanings as defined herein above, bytreatment with a reducing agent, such as sodium borohydride ortriphenylphosphine in a polar solvent, such as ethanol ortetrahydrofuran, respectively.

[0347] Thiols of formula XIV may then be treated with an alkylatingagent of the formula

Lg-(CH₂)_(p)-Q-W  (VII)

[0348] wherein p, Q and W have meanings as defined herein and Lgrepresents a leaving group, such as bromide, chloride ortrifluoromethanesulfonate, in the presence of a base, such as potassiumcarbonate or sodium hydride in an inert solvent, such asN,N-dimethylformamide or tetrahydrofuran to form compounds of formula I′in which X′ is —S—(CH₂)_(p)-Q-W, and p, Q and W have meanings definedherein.

[0349] Preferably, the alkylating agent of formula VII is selected froma group wherein p is an integer from 2 to 5, Q is O, Lg is chloride orbromide and W is

[0350] or the alkylating agent of formula VII is selected from a groupwherein p is 1 to 2, Q is a bond, Lg chloride or bromide and W is

[0351] or the alkylating agent of formula VII is selected from a groupwherein p is 2, Q is a bond, Lg chloride or bromide and W is

[0352] The alkylating agents of formula VII may be prepared usingmethods described herein or modifications thereof, or using methodsknown in the art, e.g., 4-chloromethyl-5-methyl-2-phenyloxazole and4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)-phenyl]-oxazole may beprepared using methods described in International PCT Patent ApplicationNo. WO 00/64888 or according to J. Med. Chem., Vol. 43, pp. 995-1010(2000). 1-(3-Bromopropoxy)-4-phenoxy-2-propyl-benzene may be prepared asdescribed in International PCT Patent Application No. WO 00/78312.

[0353] Preferably, alkylating agents of formula VII having the formula

[0354] wherein R_(a) and R_(b) are independently hydrogen, halogen,alkyl, alkoxy, trifluoromethyl or aryl, may be prepared by treating acompound of the formula

[0355] wherein R_(a) and R_(b) have meanings as defined for formulaVIIa, with a chlorinating agent, such as phosphorus oxychloride (POCl₃),in acetonitrile. It is essential that the reaction is carried out inacetonitrile in order to obtain alkylating agents of formula VIIa inhigh chemical yield and purity, i.e., the alkylating agents of formulaVIIa are obtained according to the present method in highregioselectivity, preferably in greater than 99% selectivity. Thechlorination is preferably conducted at an ambient temperature, e.g. atroom temperature.

[0356] Compounds of formula VIIb may be prepared by condensing analdehyde of the formula

[0357] wherein R_(a) and R_(b) have meanings as defined for formulaVIIb, with 2,3-butadione monooxime of the formula

[0358] in the presence of an acid catalyst, such as gaseous hydrochloricacid and an organic solvent, such as ethyl acetate or acetic acid,preferably glacial acetic acid, to afford compounds of formula VIIbwherein R_(a) and R_(b) have meanings as defined herein above.

[0359] In a preferred embodiment, the alkylating agent of formula VIIais 4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]-oxazole.

[0360] Alternatively, phenols of formula VI and thiols of formula XIVmay also be reacted with alcohols of the formula

HO—(CH₂)_(p)-Q-W  (VII′)

[0361] wherein p, Q and W have meanings defined herein, under Mitsunobuconditions, e.g., in the presence of triphenylphoshine and diethylazodicarboxylate in an organic solvent, such as tetrahydrofuran, toafford compounds of formula I′ in which X′ is —O—(CH₂)_(p)-Q-W or—S—(CH₂)_(p)-Q-W, respectively, and p, Q and W have meanings as definedherein. Alcohols of formula VII″ may be prepared by methods describedherein or modifications thereof, or by methods well-known in the art.

[0362] Compounds of formula I′ wherein X′ is —(CH₂)_(p)-Q-W, and p and Whave meanings as defined herein and Q represents O or S, may be obtainedby reacting compounds of the formula

[0363] wherein R, R′ and p have meanings as defined herein above, and Pgrepresents a protecting group, such as acyl, e.g., acetyl or loweralkoxycarbonyl, with chlorosulfonic acid in an inert solvent, such asdichloromethane followed by subsequent treatment with a chlorinatingagent, such as thionyl chloride or oxalyl chloride to afford sulfonylchlorides of the formula

[0364] wherein R, R′, p and Pg have meanings as defined herein above.

[0365] Sulfonyl chlorides of formula XVI may be coupled with amines offormula VI or V as described herein above to form compounds of theformula

[0366] wherein R, R′, p, Pg and L have meaning as defined herein.Subsequent removal of the protecting group using base, e.g., aqueoussodium hydroxide in a polar solvent, such as methanol, tetrahydrofuranor 1,4-dioxane, in particular when Pg is acetyl, affords alcohols of theformula

[0367] wherein R, R′, p and L have meanings as defined herein.

[0368] Alcohols of formula XVIII may be coupled with phenols of formulaW—OH or thiols of formula W—SH, e.g., under Mitsunobu conditions, toform compounds of formula I′ wherein R, R′ and L have meanings asdefined herein, and X′ represents —(CH₂)_(p)-Q-W, in which p and W havemeanings as defined herein, and Q is O or S, respectively.

[0369] Alternatively, alcohols of formula XVIII may be converted tocompounds of the formula

[0370] wherein R, R′, p and L have meanings as defined herein and Lgrepresents a leaving group, such as chloride, bromide ortrifluorosulfonate, using methods described herein or modificationsthereof, or using methods well-known in the art. Subsequent reactionwith phenols of formula W—OH or thiols of formula W—SH in the presenceof a base, such as potassium carbonate; or sodium hydride in an inertsolvent, such as N,N-dimethylformamide or tetrahydrofuran affordscompounds of formula I′ wherein R, R′ and L have meanings as definedherein, and X′ represents —(CH₂)_(p)-Q-W, in which p and W have meaningsas defined herein, and Q is O or S, respectively.

[0371] Compounds of formula I′ wherein R, R′ and L have meanings asdefined herein, and X′ represents —C(O)NR₅—(CH₂)_(p)-Q-W, and R₅, p, Qand W have meanings defined herein, may be prepared by reacting anactivated derivative of a carboxylic acid of the formula

[0372] wherein R, R′ and L have meanings as defined herein and R₁ isoptionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl,with amines or acid addition salts thereof of the formula

R₅—NH—(CH₂)_(p)-Q-W  (XXI)

[0373] wherein R₅, p, Q and W have meanings as defined herein.Carboxylic acids of formula XX and amines of formula XXI may be preparedusing methods described herein or modifications thereof, or usingmethods known in the art.

[0374] Similarly, compounds of formula I′ wherein R, R′ and L havemeanings as defined herein, and X′ represents -Z-(CH₂)_(p)—C(O)NR₆—W,and Z, p, R₆ and W have meanings as defined herein, may be prepared byreacting an activated derivative of a carboxylic acid of the formula

[0375] wherein R, R′, L, Z and p have meanings as defined herein and R₁is optionally substituted alkyl, aryl, heteroaryl, aralkyl orcycloalkyl, with amines or acid addition salts thereof of the formula

R₆—NH—W  (XXIII)

[0376] wherein R₆ and W have meanings as defined herein. Carboxylicacids of formula XXII and amines of formula XXIII may be prepared usingmethods described herein or modifications thereof, or using methodsknown in the art.

[0377] In the processes cited herein, activated derivatives ofcarboxylic acids, e.g., those of formulae XX and XXII, include acidchlorides, bromides and fluorides, mixed anhydrides, lower alkyl estersand activated esters thereof, and adducts formed with coupling agents,such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and the like. Mixed anhydrides are preferably suchfrom pivalic acid, or lower alkyl hemiesters of carbonic acids, such asethyl or isobutyl analogs. Activated esters include, for example,succinimido, phthalimido or 4-nitrophenyl esters. The reaction of anactivated derivative of a carboxylic acid, e.g., those of formulae XX orXXII, with an amine, e.g., those of formulae XXI or XXIII, respectively,may be carried out in the presence of a base, such as triethylamine,diisopropylethylamine or N-methylmorpholine in an inert solvent, such asdichloromethane, N,N-dimethylformamide or tetrahydrofuran. Carboxylicacids of formulae XX and XXII can be converted to their activatedderivatives using methods described herein or in the art.

[0378] Compounds of formula I′ wherein R, R′ and L have meanings asdefined herein, and X′ represents -Z-(CH₂)_(p)—NR₅C(O)—W,-Z-(CH₂)_(p)—NR₅C(O)NH—W or -Z-(CH₂)_(p)-NR₅C(O)O—W, and Z, p, R₅ and Whave meanings as defined herein, may be obtained by reacting amines ofthe formula

[0379] wherein R, R′, Z, p, R₅ and L have meanings as defined herein,and R₁ is optionally substituted alkyl, aryl, heteroaryl, aralkyl orcycloalkyl, with a N-derivatizing agent, such as an activated carboxylicacid derivative, an isocyanate or a chloroformate, respectively, in thepresence of a base, such as triethylamine, diisopropylethylamine orN-methylmorpholine in an inert solvent, such as dichloromethane,N,N-dimethylformamide or tetrahydrofuran. Amines of formula XXIV may beprepared using methods described herein or modifications thereof, orusing methods known in the art.

[0380] Compounds of formula I′ in which R, R′, L and X′ have meanings asdefined herein, and R₁ is optionally substituted alkyl, aryl,heteroaryl, aralkyl or cycloalkyl can be converted to compounds of theformula I′ in which R₁ is hydrogen using reaction conditions describedherein or modifications thereof, or using methods know in the art, e.g.,compounds of formula I′ in which R₁ is lower alkyl, such as methyl orethyl; may be treated with an aqueous base, such as sodium or potassiumhydroxide; in a polar solvent, such as methanol, ethanol, 1,4-dioxane ortetrahydrofuran to afford compounds of formula I′ in which R, R′, L andX′ have meanings as defined herein, and R₁ is hydrogen.

[0381] The starting compounds and intermediates which are converted tothe compounds of the invention in a manner described herein, functionalgroups present, such as amino, thiol, carboxyl and hydroxy groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected amino, thiol, carboxyl andhydroxy groups are those that can be converted under mild conditionsinto free amino, thiol, carboxyl and hydroxy groups without themolecular framework being destroyed or other undesired side reactionstaking place.

[0382] The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxy group, aminogroup, etc.), the structure and stability of the molecule of which thesubstituent is a part and the reaction conditions.

[0383] Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, N.Y. (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

[0384] The above-mentioned reactions are carried out according tostandard methods, in the presence or absence of diluent, preferably suchas are inert to the reagents and are solvents thereof, or catalysts,condensing of said other agents respectively and/or inert atmospheres,at low temperatures, room temperature or elevated temperatures(preferably at or near the boiling point of the solvents used), and atatmospheric or super-atmospheric pressure. The preferred solvents,catalysts and reaction conditions are set forth in the appendedillustrative Examples.

[0385] The invention further includes any variant of the presentprocesses, in which an intermediate product obtainable at any stagethereof is used as starting material and the remaining steps are carriedout, or in which the starting materials are formed in situ under thereaction conditions, or in which the reaction components are used in theform of their salts or optically pure antipodes.

[0386] Compounds of the invention and intermediates can also beconverted into each other according to methods generally known per se.

[0387] The invention also relates to any novel starting materials andprocesses for their manufacture.

[0388] Depending on the choice of starting materials and methods, thecompounds may be in the form of one of the possible isomers or mixturesthereof, for example, as substantially pure geometric (cis or trans)isomers, optical isomers (antipodes), racemates or mixtures thereof. Theaforesaid possible isomers or mixtures thereof are within the purview ofthis invention.

[0389] Any resulting mixtures of isomers can be separated on the basisof the physico-chemical differences of the constituents, into the puregeometric or optical isomers, diastereoisomers, racemates, for example,by chromatography and/or fractional crystallization.

[0390] Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereoisomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. The carboxylic acid intermediates can thus beresolved into their optical antipodes, e.g., by fractionalcrystallization of D- or L-(alpha-methylbenzylamine, cinchonidine,cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucineor strychnine)-salts. Racemic products can also be resolved by chiralchromatography, e.g., high pressure liquid chromatography using a chiraladsorbent.

[0391] Finally, compounds of the invention are either obtained in thefree form, or as a salt thereof if salt forming groups are present.

[0392] Acidic compounds of the invention may be converted into saltswith pharmaceutically acceptable bases, e.g., an aqueous alkali metalhydroxide, advantageously in the presence of an ethereal or alcoholicsolvent, such as a lower alkanol. From the solutions of the latter, thesalts may be precipitated with ethers, e.g., diethyl ether. Resultingsalts may be converted into the free compounds by treatment with acids.These or other salts can also be used for purification of the compoundsobtained.

[0393] Compounds of the invention having basic groups can be convertedinto acid addition salts, especially pharmaceutically acceptable salts.These are formed, for example, with inorganic acids, such as mineralacids, for example, sulfuric acid, a phosphoric or hydrohalic acid; orwith organic carboxylic acids, such as (C₁-C₄)-alkanecarboxylic acidswhich, for example, are unsubstituted or substituted by halogen, forexample, acetic acid, such as saturated or unsaturated dicarboxylicacids, for example, oxalic, succinic, maleic or fumaric acid, such ashydroxy-carboxylic acids, for example, glycolic, lactic, malic, tartaricor citric acid, such as amino acids, for example, aspartic or glutamicacid; or with organic sulfonic acids, such as (C₁-C₄)-alkyl-sulfonicacids, for example, methanesulfonic acid; or arylsulfonic acids whichare unsubstituted or substituted, for example, by halogen. Preferred aresalts formed with hydrochloric acid, methanesulfonic acid and maleicacid.

[0394] In view of the close relationship between the free compounds andthe compounds in the form of their salts, whenever a compound isreferred to in this context, a corresponding salt is also intended,provided such is possible or appropriate under the circumstances.

[0395] The compounds, including their salts, can also be obtained in theform of their hydrates, or include other solvents used for theircrystallization.

[0396] The pharmaceutical compositions according to the invention arethose suitable for enteral, such as oral or rectal; transdermal andparenteral administration to mammals, including man, for the treatmentof conditions mediated by PPAR receptors, in particular, PPARα andPPARγ. Such conditions include those conditions mentioned hereinafterwith respect to the treatment for which the compounds of the instantinvention may be employed. The said pharmaceutical compositions comprisean effective amount of a pharmacologically active compound of theinstant invention, alone or in combination with one or morepharmaceutically acceptable carriers.

[0397] The pharmacologically active compounds of the invention may beemployed in the manufacture of pharmaceutical compositions comprising aneffective amount thereof in conjunction or admixture with excipients orcarriers suitable for either enteral or parenteral application. Saidcompositions may be sterilized and/or contain adjuvants, such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure and/or buffers. Inaddition, they may also contain other therapeutically valuablesubstances. Said compositions are prepared according to conventionalmixing, granulating or coating methods, respectively, and contain about0.1-75%, preferably about 1-50%, of the active ingredient.

[0398] Suitable formulations for transdermal application include atherapeutically effective amount of a compound of the invention withcarrier. Advantageous carriers include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host.Characteristically, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound of the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

[0399] The pharmaceutical formulations contain a therapeuticallyeffective amount of a compound of the invention as defined above, eitheralone or in a combination with another therapeutic agent, e.g., each atan effective therapeutic dose as reported in the art. Such therapeuticagents include insulin, insulin derivatives and mimetics; insulinsecretagogues such as the sulfonylureas, e.g., Glipizide and Amaryl;insulinotropic sulfonylurea receptor ligands, such as meglitinides,e.g., nateglinide and repaglinide; insulin sensitizers, such as proteintyrosine phosphatase-1B (PTP-1B) inhibitors, GSK3 (glycogen synthasekinase-3) inhibitors or RXR ligands; biguanides, such as metformin;alpha-glucosidase inhibitors, such as acarbose; GLP-1 (glucagon likepeptide-1), GLP-1 analogs, such as Exendin-4, and GLP-1 mimetics; DPPIV(dipeptidyl peptidase IV) inhibitors, e.g. isoleucin-thiazolidide;DPP728 and LAF237, hypolipidemic agents, such as3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors,e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin,mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin,rosuvastatin, fluindostatin and rivastatin, squalene synthase inhibitorsor FXR (liver X receptor) and LXR (farnesoid X receptor) ligands,cholestyramine, fibrates, nicotinic acid and aspirin. A compound of thepresent invention may be administered either simultaneously, before orafter the other active ingredient, either separately by the same ordifferent route of administration or together in the same pharmaceuticalformulation.

[0400] A unit dosage for a mammal of about 50-70 kg may contain betweenabout 1 mg and 1000 mg, advantageously between about 5-500 mg of theactive ingredient. The therapeutically effective dosage of activecompound is dependent on the species of warm-blooded animal (mammal),the body weight, age and individual condition, on the form ofadministration, and on the compound involved.

[0401] The compounds of the present invention bind to PPAR receptors,and thus may be employed for the treatment of conditions mediated by thePPARs, in particular, PPARα and PPARγ. Such compounds may therefore beemployed for the treatment of dyslipidemia, hyperlipidemia,hypercholesteremia, atherosclerosis, hypertriglyceridemia, heartfailure, myocardial infarction, vascular diseases, cardiovasculardiseases, hypertension, obesity, inflammation, arthritis, cancer,Alzheimer's disease, skin disorders, respiratory diseases, ophthalmicdisorders, IBDs (irritable bowel disease), ulcerative colitis andCrohn's disease. In particular, the compounds of the present inventionmay be employed in mammals as hypoglycemic agents for the treatment andprevention of conditions in which impaired glucose tolerance,hyperglycemia and insulin resistance are implicated, such as type-1 andtype-2 diabetes, and Syndrome X.

[0402] The above-cited properties are demonstrable in vitro and in vivotests, using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. Said compounds can beapplied in vitro in the form of solutions, e.g., preferably aqueoussolutions, and in vivo either enterally, parenterally, advantageouslyintravenously, e.g., as a suspension or in aqueous solution. The dosagein vitro may range between about 10⁻⁵ molar and 10⁻¹⁰ molarconcentrations. A therapeutically effective amount in vivo may rangedepending on the route of administration, between about 1 and 500 mg/kg,preferably between about 5 and 100 mg/kg.

[0403] The compounds of the invention bind to the PPARα and PPARγreceptors and thus may be employed as dual agonists of the PPARα and thePPARγ receptors in mammals.

[0404] The activity of a compound according to the invention can beassessed by the following methods or methods well-described in the art:

[0405] The in vitro functional binding to the PPARα, PPARδ and PPARγreceptors is determined as follows:

[0406] The functional binding assays for the PPARα, PPARδ and PPARγreceptors are a variation of the coactivator-dependent receptor ligandassay (CARLA) (see Krey et al., “Fatty Acids, Eicosanoids, andHypolipidemic Agents Identified as Ligands of PeroxisomeProliferator-Activated Receptors by Coactivator-Dependent ReceptorLigand Assay”, Molecular Endocrinology, Vol. 11, pp. 779-791 (1997)).The present CARLA assays use a TR-FRET detection method previouslyreviewed (see Hemmila, “LANCE: Homogeneous Assay Platform for HTS”, J.Biomol. Screening, Vol. 4, pp. 303-307 (1999); Mathis, “HTRFTechnology”, J. Biomol. Screening, Vol. 4, pp. 309-313 (1999)). Allassays included 3 nM of the glutathione-S-transferase (GST) fusionproteins of either the hPPARα ligand binding domain (LBD) (amino acids167-468) (GST-hPPARα LBD), GST-hPPARδ LBD (amino acids 139-442) orGST-hPPARγ LBD (amino acids 175-476); 3 nM Eu-labeled anti-GST antibody(Wallac); 30 nM biotinylated steroid receptor coactivator-1 (SRC-1)peptide (an N-terminal biotinylated peptide, CPSSHSSLTERHKILHRLLQEGSPS,derived from amino acids 676-700 of SRC-1); and 10 nMstreptavidin-labelled allophycocyanin (APC; Prozyme). The binding of aligand to a PPAR LBD alters the conformation of the LBD and permits thebiotinylated SRC-1 peptide to bind. This brings the Eu-labeled anti-GSTantibody and the strepavidin-labeled APC in close proximity, therebyfacilitating fluorescence energy transfer. The biotinylated SRC-1peptide is prepared by standard solid-phase peptide synthetic methods.The GST-PPAR LBDs are expressed in pGEX vectors (Amersham Pharmacia) inthe E. coli strain BL21 (DE3) using standard expression conditions at18° C. In some cases the GST-PPAR LBDs are co-expressed with groESL. TheGST fusion proteins are purified on glutathione sepharose affinitycolumns (Amersham Pharmacia) using the method described by themanufacturer. The assay buffer contained 50 mM Tris pH 7.4, 50 mM KCl,0.1% BSA and 1 mM DTT (dithiothreitol). The assay is carried out inblack half area 96-well plates in a final volume of 25 μL. After mixingall components, the reaction mixture stands for 3 hours at roomtemperature before reading the TR-FRET (Time-Resolved FluorescenceResonance Energy Transfer) signal on a Wallac Victor 2 plate reader(measuring the ratio of signals at 665 nM and 620 nM). EC₅₀ values areestimated with the Excel add-in program XLFit (ID Business Solutions,Guildford, Surrey, UK) utilizing a 4-parameter logistic equation.

[0407] The glucose and insulin lowering activity in vivo can beevaluated as follows:

[0408] Adult male C57BL ob/ob mice (Jackson Lab, Bar Harbor, Me.) at theage of 11 weeks are housed six per cage in a reversed light cycle room(light on from 6:00 p.m. to 6:00 a.m.) and given access to Purina rodentchow and water ad libitum. On day 1, tail blood samples are taken at8:00 am and plasma glucose levels are determined. The animals arerandomly assigned to the control and compound groups. The means ofplasma glucose values of the groups were matched. Animals are thenorally dosed with vehicle (0.5% carboxymethyl-cellulose with 0.2%Tween-80) or compounds (at 30 mg/kg) in vehicle. The mice are doseddaily for a total of 3 days. On day 4, basal blood samples are taken.The plasma samples are analyzed for glucose concentrations using aYSI2700 Dual Channel Biochemistry Analyzer (Yellow Springs InstrumentCo., Yellow Springs, Ohio) and insulin concentrations using an ELISAassay.

[0409] Illustrative of the invention, the compound of Example 1demonstrates an EC₅₀ of about 27 nM in the PPARα receptor binding assay,an EC₅₀ of about 23 nM in the PPARγ receptor binding assay, and an EC₅₀of about 173 nM in the PPARδ receptor binding assay; the compound ofExample 5-10 demonstrates an EC₅₀ of about 3 nM in the PPARα receptorbinding assay, an EC₅₀ of about 3 nM in the PPARγ receptor bindingassay, and an EC₅₀ of about 1250 nM in the PPARδ receptor binding assay;and the compound of Example 6-39 demonstrates an EC₅₀ of about 7 nM inthe PPARα receptor binding assay, an EC₅₀ of about 2 nM in the PPARγreceptor binding assay, and an EC₅₀ of about 1165 nM in the PPARδreceptor binding assay. Furthermore, said compounds significantly lowerserum glucose and insulin levels after three days at a daily dose ofabout 30 mg/kg p.o. in the ob/ob mice.

[0410] The following Examples are intended to illustrate the inventionand are not to be construed as being limitations thereon. Temperaturesare given in degrees Centrigrade. If not mentioned otherwise, allevaporations are performed under reduced pressure, preferably betweenabout 15 and 100 mmHg (=20-133 mbar). The structure of final products,intermediates and starting materials is confirmed by standard analyticalmethods, e.g., microanalysis and spectroscopic characteristics, e.g.,MS, IR and NMR. Abbreviations used are those conventional in the art.

EXAMPLE 1(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid

[0411]

[0412] A.(R)-1-(4-Benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid

[0413] To a solution of (R)-2,3-dihydro-1H-indole-2-carboxylic acid(2.89 g, 14.5 mmol) and 1 N sodium hydroxide (37.7 mL, 37.7 mmol) inwater (79 mL) stirring at room temperature is added dropwise a solutionof 4-benzyloxybenzenesulfonyl chloride (4.1 g, 14.5 mmol) in dioxane(104 mL). Upon completion of the addition, the pH of the reactionmixture is monitored and maintained between 7-8 by slow addition of 1 Naqueous sodium hydroxide over the next 2 hours. The reaction mixture isstirred overnight at room temperature. The solution is poured intocrushed ice and the resulting mixture is acidified to pH 2-3 with 1 Naqueous hydrochloric acid (15 mL). The product is extracted intodichloromethane (2×150 mL). The extract is washed with water (150 mL),brine (150 mL), dried over anhydrous magnesium sulfate (MgSO₄), filteredand concentrated to give 5.5 g of(R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid as an oil: [M+1]⁺=410.32, [M−1]⁻=408.24.

[0414] B.(R)-1-(4-Benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid methyl ester

[0415] A solution of the title A compound,(R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid (5.55 g, 13.6 mmol) and p-toluenesulfonic acid monohydrate (0.52 g,2.7 mmol) in methanol (260 mL) is heated under nitrogen at reflux for 4hours. The solution is allowed to stand overnight at room temperaturewhich results in the formation of a crystalline solid. The crystals arecollected by vacuum filtration and dried at high vacuum. A second cropof crystals is obtained from the mother liquor that is isolated anddried at high vacuum. A combined yield of 3.84 g of(R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid methyl ester is obtained as a pure crystalline product:[M+1]⁺=424.27.

[0416] C.(R)-1-(4-Hydroxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid methyl ester

[0417] To a suspension of the title B compound,(R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid methyl ester (3.00 g, 7.1 mmol) in ethanol (200 mL) under nitrogenis added 10% palladium on carbon (0.3 g). The resulting mixture ishydrogenated at 46 psi for 18.5 hours at room temperature. The mixtureis filtered through celite by vacuum filtration. The filtrate isconcentrated in vacuo to give 1.31 g of(R)-1-(4-hydroxy-benzene-sulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid methyl ester which is used without further purification:[M+1]⁺=334.22, [M−1]⁻=332.16.

[0418] D.(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid methyl ester

[0419] To a solution of the title C compound,(R)-1-(4-Hydroxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid methyl ester (1.31 g, 3.9 mmol) in N,N-dimethylformamide (50 mL) atroom temperature is added anhydrous potassium carbonate (2.16 g, 15.6mmol) in one portion. After 15 minutes, a solution of3-(4-phenoxy-2-propyl-phenoxy)-propan-1-bromide (1.37 g, 3.9 mmol) inN,N-dimethylformamide (10 mL) is added at room temperature. The reactionmixture is stirred for 64 hours at room temperature. The reactionmixture is filtered, the filtrate is diluted with water (150 mL) and theresulting mixture is extracted with ether (2×150 mL). The organicextract is washed with water (3×100 mL) and brine (100 mL), dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give 2.32 g ofcrude(R)-1-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid methyl ester. Purification of the crude product by chromatography(SiO₂ ⁻: 100 g; eluant 30%→50% ethyl acetate in hexane) afforded 1.47 gof pure(R)-1-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzene-sulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid methyl ester as a colorless gum: [M+1]⁺=602.49.

[0420] E.(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid

[0421] To a mixture of the title D compound,(R)-1-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid methyl ester (1.47 g, 2.44 mmol) in methanol (50 mL) under nitrogenat room temperature is added 1 N aqueous sodium hydroxide (4.9 mL, 4.9mmol) dropwise. Upon complete addition, the mixture is stirred at roomtemperature for 45 minutes, at which time 5 mL of tetrahydrofuran isadded to facilitate the dissolution of the starting material. Themixture is stirred overnight. The reaction mixture is concentrated invacuo, the residue is partitioned between water (50 mL) and ether (50mL). The aqueous layer is separated and acidified with 1N aqueoushydrochloric acid. The product is extracted into dichloromethane. Theextract is washed with brine, dried over anhydrous sodium sulfate(Na₂SO₄), filtered and concentrated to give 1.02 g of(R)-1-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid as a white foamy solid. The solid is treated with ethanol (1 mL)which results in dissolution of the solid and upon standing crystalsstart to form. The crystals are separated and dried at high vacuum at40° C to give 0.85 9 of pure(R)-1-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid: [M+1]⁺=588.46, [M−1]⁻=586.41.

EXAMPLE 2(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid

[0422]

[0423] A. 4-Hydroxybenzenesulfonic Acid Disodium Salt

[0424] A solution of 4-hydroxybenzenesulfonic acid sodium salt dihydrate(20 g, 86 mmol) in 1N aqueous sodium hydroxide (86 mL, 86 mmol) isstirred and heated at 50-60° C. for 1 hour. The solution is concentratedin vacuo at 50° C. to give a solid. The solid is suspended in anhydroustoluene and concentrated in vacuo. This process is repeated twice. Thesolid is dried at 50° C. at high vacuum for 18 hours to give 21.34 g of4-hydroxybenzenesulfonic acid disodium salt.

[0425] B. 4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonic AcidSodium Salt

[0426] A mixture of the title A compound, 4-hydroxybenzenesulfonic aciddisodium salt (3.50 g, 16.1 mmol) and4-chloromethyl-5-methyl-2-phenyl-oxazole (4.00 g, 19.3 mmol) in 20 mL ofN,N-dimethylformamide is stirred and heated under nitrogen at 110° C.for 18 hours. The cooled reaction mixture is filtered and the solidobtained is washed thoroughly with dichloromethane. The solid is driedovernight to give 1.42 g of4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonic acid sodiumsalt: [M+1]⁺=346.05, [M−1]⁻=344.02.

[0427] C. 4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylchloride

[0428] To a solution of thionyl chloride (8.0 mL) and 2 drops ofN,N-dimethylformamide stirring under nitrogen at 0C is added the title Bcompound, 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonic acidsodium salt (1.42 g, 3.8 mmol) in one portion. The resulting suspensionis stirred at 0° C. for 10 minutes. The ice bath is removed and thesuspension is stirred at room temperature for 1.5 hours. Three moredrops of N,N-dimethyl-formamide is added, after which a clear solutionresults upon stirring for an additional hour. The solution isconcentrated under vacuo to a solid residue. The residue is partitionedbetween water (20 mL) and ethyl acetate (20 mL). The organic layer isseparated and washed successively with water (3×20 mL), 0.1N aqueoussodium hydroxide (3×20 mL) and brine (20 mL). The organic layer is driedover anhydrous MgSO₄, filtered and concentrated in vacuo to give an oilwhich slowly solidifies to give 0.48 9 of4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride:[M+1]⁺=363.99.

[0429] D.(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid

[0430] To a solution of the title C compound,(R)-2,3-dihydro-1H-indole-2-carboxylic acid hydrochloride (0.92 g, 4.6mmol), 1N aqueous sodium hydroxide (12.0 mL, 12 mmol) and water (25 mL)at room temperature is added dropwise a solution of4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride (1.65g, 4.6 mmol) in dioxane (33 mL). Upon completion of the addition, the pHof the reaction mixture is monitored and maintained between 7-8 by slowaddition of 1N aqueous sodium hydroxide over the next 2 hours. Thereaction mixture is stirred overnight at room temperature. The solutionis poured into crushed ice and the resulting mixture is acidified to pH2-3 with 1N aqueous hydrochloric acid (11 mL). The precipitate thatforms is collected, washed with water and dried under high vacuumovernight to give 1.5 g of(R)-1-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid: [M+1]⁺=491.2, [M−1]⁻=489.1

EXAMPLE 3(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid

[0431]

[0432] A. 4,4′-Dithiobisbenzenesulfonic acid

[0433] To a solution of phenyl disulfide (4.36 g, 20 mmol) indichloromethane (40 mL) at 0° C. is added a solution of chlorosulfonicacid (4.64 g, 2.95 mL, 40 mmol) in dichloromethane (60 mL) dropwise. Themixture is stirred at 0° C. for 1 hour followed by 1.5 hours at roomtemperature. The reaction mixture is concentrated to dryness in vacuoand the residue is partitioned between diethyl ether and water. Thewater phase is separated, made basic with 2N aqueous sodium hydroxideand concentrated in vacuo to half the volume. The resulting solution isrefrigerated overnight. The precipitate formed overnight is discarded,the filtrate is concentrated further in vacuo until a solid started toappear. The mixture is placed in the refrigerator for 2 hours. Themixture is treated with ethanol, the solid formed is filtered, washedwith ethanol twice and dried under high vacuum overnight at roomtemperature to give 6.0 g of 4,4′-dithiobisbenzenesulfonic acid as awhite solid: [M−1]⁻=398.8.

[0434] B. 4,4′-Dithiobisbenzenesulfonyl chloride

[0435] To thionyl chloride (70 mL) at 0° C. is added the title Acompound, 4,4′-dithiobis-benzenesulfonic acid (5.9 g, 14 mmol)portionwise followed by N,N-dimethylformamide (1.4 mL). The resultingmixture is stirred at room temperature for 5 hours. The reaction mixtureis concentrated to dryness in vacuo and treated with ethyl acetatefollowed by ice and water. The organic phase is separated, washed withwater, saturated sodium bicarbonate and brine, dried over sodium sulfateand concentrated in vacuo to give 4.0 g of 4,4′-dithiobisbenzenesulfonylchloride as a tan solid.

[0436] C.4,4′-Dithiobis-[(R)-1-benzenesulfonyl-2,3-dihydro-1H-indole-2-carboxylicacid]

[0437] To a solution of (R)-2,3-dihydro-1H-indole-2-carboxylic acidhydrochloride (4.35 g, 21.7 mmol), 1N aqueous sodium hydroxide (43.5 mL,43.5 mmol) and water (20 mL) at 0° C. is added dropwise a solution ofthe title B compound, 4,4′-dithiobisbenzenesulfonyl chloride (3.0 g,7.24 mmol) in dioxane (60 mL). Upon completion of the addition, the pHof the reaction mixture is monitored and maintained between 7-8 by slowaddition of 1N aqueous sodium hydroxide over the next 2 hours. Thereaction mixture is stirred overnight at room temperature. The reactionmixture is filtered, the filtrate is poured into crushed ice and theresulting mixture is acidified to pH 2-3 with 1N aqueous hydrochloricacid. The mixture is extracted with ethyl acetate, the organic phase iswashed with 1N aqueous hydrochloric acid, water, brine and dried oversodium sulfate and concentrated in vacuo to give 4.0 g of4,4′-dithiobis-(1-benzenesulfonyl-2,3-dihydro-1H-indole-2-carboxylicacid) as a foamy solid: [M−1]⁻=667.25.

[0438] D.(R)-1-(4-Mercapto-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid

[0439] To a solution of sodium borohydride (0.185 g, 4.86 mmol) inethanol (60 mL) at 0° C. is added the title C compound,4,4′-dithiobis-(1-benzenesulfonyl-2,3-dihydro-1H-indole-2-carboxylicacid) (0.65 g, 0.973 mmol) portionwise. The reaction mixture is stirredat room temperature overnight. The mixture is treated with ice/water,acidified with 2N aqueous hydrochloric acid and extracted into ethylacetate. The combined organic extracts are washed with water and brine,dried over sodium sulfate and concentrated in vacuo to give 0.63 g of(R)-1-(4-mercapto-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid as a gum: [M−1]⁻=333.9.

[0440] E.(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid

[0441] To a solution of the title D compound,(R)-1-(4-mercapto-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylicacid (0.56 g, 1.67 mmol) in dioxane (8 mL) is added 1N aqueous sodiumhydroxide (3.4 mL) and water (2 mL) at room temperature. The resultingsolution is treated dropwise with a solution of4-chloromethyl-5-methyl-2-phenyl-oxazole (0.423 g, 2.04 mmol) in dioxane(4 mL). After stirring 1.5 hours, the reaction mixture is concentratedto near dryness in vacua. The residue is taken into water, the aqueousphase is washed with ether, acidified with 2N aqueous hydrochloric acidand extracted into ethyl acetate. The combined organic phases are washedwith water, brine and dried over sodium sulfate. The organic phase isconcentrated in vacuo and dried overnight at high vacuum to give 0.68 gof(R)-1-[4-(5-methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid as gum: [M−1]⁻=504.9.

EXAMPLE 4

[0442] The following compounds are prepared analogously to Example 1 bytreating the title C compound in Example 1 with the appropriatealkylating agent, or by following the protocol described in Examples 2or 3:

Compd R Z p Q W MS [m/z] 4-1 H O 5 O

620.1 [M − 1]⁻ 4-2 H O 4 O as above 606.48 [M − 1]⁻ 4-3 H O 3 O as above592.21 [M − 1]⁻ 4-4 H O 2 O as above 578.18 [M − 1]⁻ 4-5 H O 3 O

562.20 [M − 1]⁻ 4-6 Cl O 3 O as above 596.10 [M − 1]⁻ 4-7 OMe O 3 O asabove 594.37 [M + 1]⁺ 4-8 H O 3 O

576.15 [M − 1]⁻ 4-9 H O 4 O

600.21 [M − 1]⁻ 4-10 MeO O 3 O as above 616.30 [M − 1]⁻ 4-11 Cl O 3 O asabove 620.10 [M − 1]⁻ 4-12 n-Pr O 3 O as above 4-13 H O 2 O as above591.3 [M + 1]⁺ 4-14 H O 2 a bond

503.10 [M − 1]⁻ 4-15 Cl O 2 a bond as above 537.0 [M − 1]⁻ 4-16 MeO O 1a bond as above 520.99 [M + 1]⁺ 4-17 Cl O 1 a bond as above 525.04 [M +1]⁺ 4-18 n-Pr O 1 a bond as above 533.10 [M + 1]⁺ 4-19 H O 1 a bond

559.10 [M + 1]⁺ 4-20 H S 1 a bond as above 575.29 [M + 1]⁺ 4-21 H O 1 abond

507.0 [M − 1]⁻ 4-22 H S 1 a bond as above 525.36 [M + 1]⁺ 4-23 H O 1 abond

626.94 [M + 1]⁺ 4-24 H S 1 a bond as above 642.90 [M + 1]⁺

EXAMPLE 5

[0443] The following compounds are prepared analogously to the previousexamples:

Compd R Z p Q W MS [m/z] 5-1 H O 5 O

557.97 [M − 1]⁻ 5-2 H O 4 O as above 544.28 [M − 1]⁻ 5-3 H O 3 O asabove 529.97 [M − 1]⁻ 5-4 H O 2 O as above 516.29 [M − 1]⁻ 5-5 H O 4 O

540.07 [M + 1]⁺ 5-6 H O 3 O as above 526.24 [M + 1]⁺ 5-7 H O 3 O

548.18 [M − 1]⁻ 5-8 H O 3 O

514.2 [M − 1]⁻ 5-9 H O 2 a bond

441.16 [M − 1]⁻ 5-10 H O 1 a bond as above 427.11 [M − 1]⁻ 5-11 H O 1 abond

497.0 [M + 1]⁺ 5-12 H O 1 a bond

445.0 [M + 1]⁺ 5-13 H O 1 a bond

562.98 [M + 1]⁺

EXAMPLE 6

[0444] The following compounds are prepared analogously to previousexamples or using methods described herein:

Compd R Z p Q W MS [m/z] 6-1 H —C(O)NH— 1 a bond

455.22 [M − 1]⁻ 6-2 H a bond 2 —C(O)NH—

439.04 [M + 1]⁺ 6-3 H a bond 2 —C(O)NH—

471 47 [M + 1]⁺ 6-4 H a bond 2 —C(O)NH—

471.19 [M + 1]⁺ 6-5 H a bond 2

489.24 [M − 1]⁻ 6-6 H a bond 2 —C(O)NMe—

421.1 [M − 1]⁻ 6-7 H a bond 2

427.18 [M − 1]⁻ 6-8 H a bond 2

441.15 [M − 1]⁻ 6-9 H O 2 —NMe—

443.96 [M − 1]⁻ 6-10 H O 5 O

572.39 [M − 1]⁻ 6-11 H O 4 O as above 558.43 [M − 1]⁻ 6-12 H O 3 O asabove 544.2 [M − 1]⁻ 6-13 H O 2 O as above 530.34 [M − 1]⁺ 6-14 H O 3 O

516.2 [M + 1]⁺ 6-15 MeO O 3 O as above 546.38 [M + 1]⁺ 6-16 Cl O 3 O asabove 550.1 [M + 1]⁺ 6-17 n-Pr O 3 O as above 558.46 [M + 1]⁺ 6-18 H O 2O as above 502.0 [M + 1]⁺ 6-19 H O 3 O

460.2 [M + 1]⁺ 6-20 H O 3 O

446.2 [M + 1]⁺ 6-21 H O 3 O

566.0 [M + 1]⁺ 6-22 H O 3 O

528.28 [M − 1]⁻ 6-23 H O 4 O

554.13 [M + 1]⁺ 6-24 H O 3 O as above 540.07 [M + 1]⁺ 6-25 MeO O 3 O asabove 570.06 [M + 1]⁺ 6-26 Cl O 3 O as above 572.27 [M + 1]⁺ 6-27 n-Pr O3 O as above 582.20 [M + 1]⁺ 6-28 H O 2 O as above 526.20 [M + 1]⁺ 6-29H S 3 O as above 554.1 [M + 1]⁺ 6-30 H S 2 O as above 540.2 [M + 1]⁺6-31 H a bond 3 O as above 524.0 [M + 1]⁺ 6-32 H O 3 O

608.0 [M + 1]⁺ 6-33 H O 2 O as above 594.0 [M + 1]⁺ 6-34 H O 3 O

562.39 [M − 1]⁻¹ 6-35 Cl O 3 O as above 598.29 [M + 1]⁺ 6-36 H O 2 abond

455.14 [M − 1]⁻ 6-37 MeO O 2 a bond as above 487.10 [M + 1]⁺ 6-38 Cl O 2a bond as above 491.2 [M + 1]⁺ 6-39 H O 1 a bond as above 441.09 [M −1]⁻ 6-40 MeO O 1 a bond as above 473.10 [M + 1]⁺ 6-41 Cl O 1 a bond asabove 477.0 [M + 1]⁺ 6-42 n-Pr O 1 a bond as above 484.93 [M + 1]⁺ 6-43H S 2 a bond as above 471.0 [M − 1]⁻ 6-44 H S 1 a bond as above 459.0[M + 1]⁺ 6-45 H O 2 a bond

522.95 [M − 1]⁻ 6-46 H O 1 a bond as above 511.0 [M + 1]⁺ 6-47 H S 1 abond as above 527.1 [M + 1]⁺ 6-48 H O 1 a bond

459.10 [M − 1]⁻ 6-49 H S 1 a bond as above 477.10 [M + 1]⁺ 6-50 H O 1 abond

577.01 [M − 1]⁻ 6-51 H S 1 a bond as above 593.29 [M − 1]⁻ 6-52 H O 1 abond

517.0 [M − 1]⁻ 6-53 H O 1 a bond

6-54 H S 2 a bond as above 6-55 H S 1 a bond as above 6-56 H O 2 a bond

431.08 [M − 1]⁻ 6-57 H O 2 a bond

447.07 [M − 1]⁻

EXAMPLE 7 4-Chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]-oxazole

[0445]

[0446] A. 4,5-Dimethyl-2-[4-(trifluoromethyl)phenyl]-oxazole 3-oxide,hydrochloride salt

[0447] Into a solution of 4-trifluoromethyl benzaldehyde (400.0 g, 2.3mol) and 2,3-butanedione monoxime (212 g, 2.055 mol) in 800 mL ofglacial acetic acid at 2-5° C., hydrogenchloride gas (250 g) is slowlybubbled for 1.5 hours. The mixture is stirred at the same temperaturefor 1 hour further. 3.75 L of t-butyl methyl ether are added whilemaintaining the temperature between 5-25° C. (first 400 mL addition isexothermic). The resulting suspension is stirred for 30 minutes, thencooled to 10° C. and the solids are collected by filtration. The filtercake is washed with 500 mL of t-butylmethyl ether, and dried at 55-60°C. (20 mbar) for 18 hours to afford 550 g (91% yield) of4,5-dimethyl-2-[4-(trifluoromethyl)phenyl]-oxazole 3-oxide,hydrochloride salt: m.p. 182-184° C. (with decomposition).

[0448] B. 4-Chloromethyl-5-methyl-2-[4(trifluoromethyl)phenyl]-oxazole

[0449] The suspension of the title A compound,4,5-dimethyl-2-(4-trifluoromethylphenyl)-oxazole 3-oxide hydrochloride(500 g, 1.70 mol) in 4.06 L of acetonitrile is stirred for 15 minutes atroom temperature, then cooled to 10° C. 491 9 (3.17 mol) of POCl₃ areadded at 15° C. over a period of 30 minutes. The suspension is stirredat room temperature for 16 hours, and the mixture is cooled to 10° C.,and 6 L of water are added into the reaction mixture slowly (first 400mL of water addition is very exothermic). The suspension is then stirredat room temperature for 6 hours further, and the solids are collected byfiltration, washed with 2 L of water and dried to a constant weight at50° C. (20 mbar) to afford4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]-oxazole as a whitesolid (400 g, 85% yield): m.p. 97-98° C.

1: A compound of the formula

wherein L is

 radical in which R₁ is hydrogen, optionally substituted alkyl, aryl,heteroaryl, aralkyl or cycloalkyl; R₂ is hydrogen, hydroxy, optionallysubstituted alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, alkylthio,arylthio or aralkylthio; R₃ is hydrogen or aryl; or R₂ and R₃ combinedare alkylene which together with the carbon atoms they are attached toform a 5- to 7-membered ring; n is zero or an integer from 1 to 2; Y ishydrogen; or Y and R₂ taken together with the carbon atoms they areattached to form a bond provided that n is 1; R₄ is hydrogen; or R₄ andY taken together with the carbon atoms they are attached to form a bondprovided that n is 1, and R₂ and R₃ taken together with the carbon atomsthey are attached to form a bond; or L is

 radical in which R₁ is hydrogen, optionally substituted alkyl, aryl,heteroaryl, aralkyl or cycloalkyl; R″ is hydrogen, optionallysubstituted alkyl, alkoxy or halogen; m is an integer from 1 to 2; Y ishydrogen; R₄ is hydrogen; or R₄ and Y taken together with the carbonatoms they are attached to form a bond provided that m is 1; R and R′are independently hydrogen, halogen, optionally substituted alkyl,alkoxy, aralkyl or heteroaralkyl; or R and R′ combined together form amethylenedioxy group provided that R and R′ are attached to carbon atomsadjacent to each other; or R and R′ combined together with the carbonatoms they are attached to form an optionally substituted 5- to6-membered aromatic or heteroaromatic ring provided that R and R′ areattached to carbon atoms adjacent to each other; or R—C and R′—C mayindependently be replaced by nitrogen; X is -Z-(CH₂)_(p)-Q-W wherein Zis a bond, O, S, —C(O)— or —C(O)NR₅— in which R₅ is hydrogen, alkyl oraralkyl; p is an integer from 1 to 8; Q is a bond provided that Z is nota bond when p is 1; or Q is —O(CH₂)_(r)— or —S(CH₂)_(r)—, in which r iszero or an integer from 1 to 8; or Q is —O(CH₂)₁₋₈O—, —S(CH₂)₁₋₈O—,—S(CH₂)₁₋₈S—, —C(O)— or —C(O)NR₆— in which R₆ is hydrogen, optionallysubstituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl orheteroaralkyl; or Q is —NR₆—, —NR₅C(O)—, —NR₅C(O)NH— or —NR₅C(0)O—provided that p is not 1; W is cycloalkyl, aryl, heterocyclyl, aralkylor heteroaralkyl; or W and R₆ taken together with the nitrogen atom towhich they are attached form a 8- to 12-membered bicyclic ring, whichmay be optionally substituted or may contain another heteroatom selectedfrom oxygen, nitrogen and sulfur; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomersthereof. 2: A compound according to claim 1 of the formula

wherein L is

 radical in which R₁ is hydrogen or optionally substituted alkyl; R₂ andR₃ are hydrogen; or R₂ and R₃ combined are alkylene which together withthe carbon atoms they are attached to form a 6-membered ring; n is zeroor an integer from 1 to 2; Y is hydrogen; R₄ is hydrogen; or L is

 radical in which R₁ is hydrogen or optionally substituted alkyl; R″ ishydrogen, optionally substituted alkyl, alkoxy or halogen; m is aninteger from 1 to 2; Y is hydrogen; R₄ is hydrogen; R and R′ areindependently hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy; or R and R′ combined together form a methylenedioxy groupprovided that R and R′ are attached to carbon atoms adjacent to eachother; Z is a bond, O, S or —C(O)NR₅— in which R₅ is hydrogen, alkyl oraralkyl; p is an integer from 1 to 5; Q is a bond provided that Z is nota bond when p is 1; or Q is —O(CH₂)_(r)— or —S(CH₂)_(r)— in which r iszero; or Q is —C(O)— or —C(O)NR₆— in which R₆ is hydrogen, optionallysubstituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl orheteroaralkyl; or Q is —NR₆—, —NR₅C(O)—, —NR₅C(O)NH— or —NR₅C(O)O—provided that p is not 1; W is cycloalkyl, aryl or heterocyclyl; or Wand R₆ taken together with the nitrogen atom to which they are attachedform a 9- to 10-membered bicyclic ring, which may be optionallysubstituted or may contain another heteroatom selected from oxygen,nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; oran optical isomer thereof; or a mixture of optical isomers thereof. 3: Acompound according to claim 2, wherein L is

 radical in which R₁ is hydrogen or optionally substituted alkyl; R₂ andR₃ are hydrogen; n is zero or an integer from 1 to 2; or L is

 radical in which R₁ is hydrogen or optionally substituted alkyl; R″ ishydrogen; m is an integer from 1 to 2; R is hydrogen, halogen,optionally substituted C₁₋₆alkyl or C₁₋₆alkoxy; R′ is hydrogen; Z is abond, O or S; p is an integer from 1 to 5; Q is a bond provided that Zis not a bond when p is 1; or Q is O, S or —C(O)NR₆— in which R₆ ishydrogen, optionally substituted alkyl or cycloalkyl; or Q is —NR₆—,—NR₅C(O)NH— or —NR₅C(O)O— in which R₅ is hydrogen, alkyl or aralkylprovided that p is not 1; W is cycloalkyl, aryl or heterocyclyl; or Wand R₆ taken together with the nitrogen atom to which they are attachedform a 9- to 10-membered bicyclic ring, which may be optionallysubstituted or may contain another heteroatom selected from oxygen,nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; oran optical isomer thereof; or a mixture of optical isomers thereof. 4: Acompound according to claim 3 of the formula

wherein L is

 radical in which R₁ is hydrogen or optionally substituted alkyl; n iszero or 1; or L is

 radical in which R₁ is hydrogen or optionally substituted alkyl; m is1; R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy; Z is a bond, O or S; p is an integer from 1 to 5; Q is abond provided that Z is not a bond when p is 1; or Q is O, S or—C(O)NR₆— in which R₆ is hydrogen, optionally substituted alkyl orcycloalkyl; or Q is —NR₆—, —NR₅C(O)NH— or —NR₅C(O)O— in which R₅ ishydrogen, alkyl or aralkyl provided that p is not 1; W is cycloalkyl,aryl or heterocyclyl; or W and R₆ taken together with the nitrogen atomto which they are attached form a 9- to 10-membered bicyclic ring, whichmay be optionally substituted or may contain another heteroatom selectedfrom oxygen, nitrogen and sulfur; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomersthereof. 5: A compound according to claim 4, wherein L is

 radical in which R₁ is hydrogen; and n is zero or 1; R is hydrogen,halogen, optionally substituted C₁₋₆alkyl or C₁₋₆alkoxy; Z is a bond, Oor S; p is an integer from 1 to 4; Q is a bond provided that Z is not abond when p is 1; or Q is O or S; W is aryl or heterocyclyl; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers thereof. 6: A compound according toclaim 4, wherein L is

 radical in which R₁ is hydrogen; R is hydrogen, halogen, optionallysubstituted C₁₋₆alkyl or C₁₋₆alkoxy; Z is a bond, O or S; p is aninteger from 1 to 4; Q is a bond provided that Z is not a bond when p is1; or Q is O or S; W is aryl or heterocyclyl; or a pharmaceuticallyacceptable salt thereof; or an optical isomer thereof; or a mixture ofoptical isomers thereof. 7: A compound according to claim 4, wherein theasymmetric center in radical L is in the (R) configuration; or apharmaceutically acceptable salt thereof. 8: A compound according toclaim 4, wherein R₁ is hydrogen or optionally substituted alkyl; R ishydrogen, halogen, optionally substituted C₁₋₆alkyl or C₁₋₆alkoxy; Z isO or S; p is 2; Q is a —NR₆— in which R₆ is lower alkyl; W is aryl orheterocyclyl; or a pharmaceutically acceptable salt thereof; or anoptical isomer thereof; or a mixture of optical isomers thereof. 9: Acompound according to claim 8, wherein R is hydrogen, chloro, n-propylor methoxy; or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof. 10: A compoundaccording to claim 4, wherein R₁ is hydrogen or optionally substitutedalkyl; R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy; Z is a bond; p is 2; Q is a —C(O)NR₆— in which R₆ isoptionally substituted alkyl; W is aryl or heterocyclyl; or W and R₆taken together with the nitrogen atom to which they are attached form a9- to 10-membered bicyclic ring, which may be optionally substituted ormay contain another heteroatom selected from oxygen, nitrogen andsulfur; or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof. 11: A compoundaccording to claim 10, wherein R is hydrogen, chloro, n-propyl ormethoxy; or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof. 12: A compoundaccording to claim 4, wherein R₁ is hydrogen or optionally substitutedalkyl; R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy; Z is a bond, O or S; p is an integer from 2 to 3; Q is O orS; W is aryl or heterocyclyl; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomersthereof. 13: A compound according to claim 12, wherein R is hydrogen,chloro, n-propyl or methoxy; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomersthereof. 14: A compound according to claim 12, wherein W is selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers thereof. 15: A compoundaccording to claim 4, wherein R₁ is hydrogen or optionally substitutedalkyl; R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy; Z is O or S; p is an integer from 1 to 2; Q is a bond; W isaryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; oran optical isomer or a mixture of optical isomers thereof. 16: Acompound according to claim 15, wherein R is hydrogen, chloro, n-propylor methoxy; or a pharmaceutically acceptable salt thereof; or an opticalisomer thereof; or a mixture of optical isomers thereof. 17: A compoundaccording to claim 15, wherein W is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers thereof. 18: A compoundaccording to claim 15, wherein R₁ is hydrogen or optionally substitutedalkyl; R is hydrogen, halogen, optionally substituted C₁₋₆alkyl orC₁₋₆alkoxy; Z is O or S; p is 2; Q is a bond; W is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers thereof. 19: A compoundaccording to claim 1, which is selected from the group consisting of:(R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-azetidine-2-carboxylicacid;(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-azetidine-2-carboxylicacid;(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-azetidine-2-carboxylicacid;(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-azetidine-2-carboxylicacid;(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol4-ylmethoxy]-benzenesufonyl}-azetidine-2-carboxylicacid;(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene-sulfonyl}-azetidine-2-carboxylicacid;(R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-azetidine-2-carboxylicacid;(R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-(4-{3-[2-Propyl-4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}-benzenesulfonyl)-pyrrolidine-2-carboxylicacid;(R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-(4-{2-[2-Propyl-4-(4-trifluoromethyl-phenoxy)-phenoxy]-ethoxy}-benzenesufonyl)-pyrrolidine-2-carboxylicacid;(R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-3-propyl-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propylsulfanyl]-benzenesufonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene-sulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-[4-(2-Biphenyl4-yl-5-methyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;(R)-1-[3-Methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;(R)-1-[3-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-3-propyl-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-pyrrolidine-2-carboxylicacid;(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{3-Methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{3-Chloro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-(4-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-benzenesufonyl)-pyrrolidine-2-carboxylicacid;(R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylsulfanyl]-benzenesulfonyl}-pyrrolidine-2-carboxylicacid;(R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene-sulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-[3-Methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-[3-Chloro-4-(5-methyl-2-phenyI-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-3-propyl-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{3-Chloro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid;(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzene-sulfonyl}-pyrrolidine-2-carboxylicacid; and(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzene-sulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid; or a pharmaceutically acceptable salt thereof; or an enantiomerthereof; or a mixture of enantiomers thereof. 20: A method for theactivation of Peroxisome Proliferator-Activated Receptors (PPAR) whichmethod comprises administering to a mammal in need thereof atherapeutically effective amount of a compound of claim
 1. 21: A methodfor the treatment of conditions mediated by PPARs which method comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of claim
 1. 22: The method according to claim 21,which method comprises administering said compound in combination with atherapeutically effective amount of insulin, insulin derivative ormimetic; insulin secretagogue; insulinotropic sulfonylurea receptorligand; insulin sensitizer; biguanide; alpha-glucosidase inhibitors;GLP-1, GLP-1 analog or mimetic; DPPIV inhibitor; HMG-CoA reductaseinhibitor; squalene synthase inhibitor; FXR or LXR ligand;cholestyramine; fibrates; nicotinic acid or aspirin. 23: A method forthe treatment of dyslipidemia, hyperlipidemia, hypercholesteremia,atherosclerosis, hypertriglyceridemia, heart failure, myocardialinfarction, vascular diseases, cardiovascular diseases, hypertension,obesity, Syndrome-X, inflammation, arthritis, cancer, Alzheimersdisease, skin disorders, respiratory diseases, ophthalmic disorders,inflammatory bowel diseases, ulcerative colitis and Crohn's disease,type-1 and type-2 diabetes which method comprises administering to amammal in need thereof a therapeutically effective amount of a compoundof claim
 1. 24: A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 in combinationwith one or more pharmaceutically acceptable carriers. 25: Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 in combination with a therapeutically effectiveamount of insulin, insulin derivative or mimetic; insulin secretagogue;insulinotropic sulfonylurea receptor ligand; insulin sensitizer;biguanide; alpha-glucosidase inhibitors; GLP-1, GLP-1 analog or mimetic;DPPIV inhibitor; HMG-CoA reductase inhibitor; squalene synthaseinhibitor; FXR or LXR ligand; cholestyramine; fibrates; nicotinic acid;or aspirin. 26: A pharmaceutical composition according to claim 24 forthe treatment of dyslipidemia, hyperlipidemia, hypercholesteremia,atherosclerosis, hypertriglyceridemia, heart failure, myocardialinfarction, vascular diseases, cardiovascular diseases, hypertension,obesity, Syndrome-X, inflammation, arthritis, cancer, Alzheimer'sdisease, skin disorders, respiratory diseases, ophthalmic disorders,inflammatory bowel diseases, ulcerative colitis and Crohn's disease,impaired glucose tolerance, hyperglycemia, insulin resistance, type-1and type-2 diabetes. 27: A method for the preparation of alkylatingagents of the formula

wherein R_(a) and R_(b) are independently hydrogen, halogen, alkyl,alkoxy, trifluoromethyl or aryl; wherein the method comprises treating acompound of the formula

wherein R_(a) and R_(b) have meanings as defined for formula VIIa; witha chlorinating agent in acetonitrile. 28: The method according to claim27, wherein the chlorinating agent is phosphorus oxychloride. 29: Themethod according to claim 27, wherein the alkylating agent of formulaVIIa is 4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]-oxazole.30: The method according to claim 27, wherein a compound of formula VIIbis prepared by condensing an aldehyde of the formula

wherein R_(a) and R_(b) have meanings as defined in said claim; with2,3-butadione monooxime of the formula

in the presence of an acid catalyst and an organic solvent; to affordcompounds of formula VIIb. 31: The method according to claim 30, whereinthe acid catalyst is gaseous hydrochloric acid and the organic solventis glacial acetic acid. 32: A pharmaceutical composition according toclaim 25 for the treatment of dyslipidemia, hyperlipidemia,hypercholesteremia, atherosclerosis, hypertriglyceridemia, heartfailure, myocardial infarction, vascular diseases, cardiovasculardiseases, hypertension, obesity, Syndrome-X, inflammation, arthritis,cancer, Alzheimer's disease, skin disorders, respiratory diseases,ophthalmic disorders, inflammatory bowel diseases, ulcerative colitisand Crohn's disease, impaired glucose tolerance, hyperglycemia, insulinresistance, type-1 and type-2 diabetes.